The invention relates to radiolabeled renal agents and more particularly to a technetium-99m-labeled renal agent.
Radionuclidic techniques may provide assessment of glomerular filtration rate (GFR), effective renal plasma flow (ERPF), or individual renal functions. Several agents are currently available for determination of these diagnostic parameters, however, the formulation of a technetium-99m-labeled agent for such determinations has heretofore not been totally satisfactory.
The current tracer of choice for the clinical evaluation of renal tubular function is o-[.sup.131 I]iodohippurate (OIH). Unfortunately, it has the disadvantage of imparting a relatively high absorbed radiation dose to the patient at low diagnostic doses and thus presents a health risk. The radiation dose at 3 hrs after intravenous administration of 500 uCi of I-131 OIH is 47 mrad to a normal kidney and 1.7 rad to the bladder wall. Renal absorbed doses of 3 rad or higher may be encountered in patients with impaired renal function. Although I-123-labeled OIH lowers the radiation dose, it is not available at a reasonable cost for routine use. In addition, the presence of varying amounts of free radioiodine in OIH preparations often poses problems for accurate quantifiable assessment of function.
Technetium-99m (Tc-99m) has ideal physical properties for many applications in nuclear medicine, by virtue of its short half-life and favorable radiation characteristics. The low radiation dose permits the administration of large amounts of activity within short time intervals for serial measurements. Several Tc-99m agents have been reported for use in renal imaging and perfusion studies. Tc-99m diethylenetriaminepentaacetic acid (DTPA) is widely used in clinical nuclear medicine for GFR measurements. Ethylenediaminetetraacetic acid (EDTA) or DTPA complexes of Tc-99m are excreted solely through the slower process of glomerular filtration, and their slow rate of excretion, relative to that of compounds that are actively excreted, is a serious disadvantage. Tc-99m-labeled agents that are cleared rapidly by active tubular excretion, with minimal or preferably no reabsorption from the tubular lumen, would provide significant advantages over the agents mentioned above. They would be excreted within a short time interval, yielding a high target-to-background ratio and minimal radiation dose.
A new class of chelating agents, Tc-99m-DADS [N,N'-bis(mercaptoacetamido)ethylene diamine and its propionic acid derivative], has been reported to have rapid renal excretion consistent with tubular excretion. The renal excretion of DADS is greater than that of Tc-99m DTPA, but lower than that of OIH in rodents. DADS is inferior to OIH in terms of specificity and rate of excretion in normals, and especially in patients with elevated levels of creatinine. The significant biliary excretion of DADS in rats and humans represents a major limitation to its use.
Another class of chelating agents, mercaptoacetyl glycyl-glycyl-glycine (MAG.sub.3) based on a triamide monomercaptide tetradentate set of donor groups, is reported to yield a Tc-99m complex which has renal clearance similar to OIH and comparable performance in animal and human studies. However, purification of the Tc-99m-MAG.sub.3 complex by high performance liquid chromatography (HPLC) is required prior to its clinical use. The complicated preparatory procedure for these agents, requiring heating and a HPLC purification step to separate the component that shows optimal renal excretion kinetics, precludes their use in a routine clinical setting.
Accordingly, it is an object of the present invention to provide a novel compound and a method of making the same.
It is also an object of the present invention to provide an improved Tc-99m labeled renal agent which overcomes the serious disadvantages inherent in renal agents presently available.
Another object of the present invention is to provide an improved Tc-99m labeled renal agent which is excreted within a relatively short time interval and which yields a high target-to-background ratio with minimal radiation dose.
A further object of the present invention is to provide an improved Tc-99m labeled renal agent which does not require a complicated mode of preparation and therefore may be used in a routine clinical setting.
An additional object of the present invention is to provide a Tc-99m labeled renal agent which is stable.
It is also an object to provide a Tc-99m labeled renal agent which is less of a health risk to the patient from radioactivity than OIH and provides a better target-to-background ratio than Tc-99m labeled MAG.sub.3.